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Objective: Co-morbid diagnoses, such as disruptive behavior disorders (DBDs) and high levels of aggression, are extremely common among youth with pediatric bipolar disorder (PBD) and may interfere with treatment response; however, they have rarely been examined as predictors of response to pharmacotherapy. The current study examines co-morbid DBD and aggression prospectively as predictors of pharmacotherapy outcome, as well as potential moderators of response to a specific medication (risperidone vs. divalproex), among children with PBD.Methods: Data are from a prospective 6-week double-blind, placebo-controlled, randomized outpatient medication treatment trial of risperidone versus divalproex for manic episodes in 65 children 8-18 with PBD. Outcome measures were administered at pretest, post-test, and weekly during the 6 weeks of treatment. Mixed-effects regression models were used to examine pharmacotherapy response.Results: Results indicated that youth with co-morbid DBD experienced greater improvement in manic symptoms in response to risperidone versus divalproex, whereas youth with non-co-morbid DBD experienced similar trajectories of symptom improvement in both medication groups. In addition, the non-DBD group experienced greater improvement in global functioning over time as compared with youth with co-morbid-DBD, and this gap increased over the course of treatment. Results also indicated that high-aggression youth experienced worse global functioning by end treatment versus low-aggression youth.Conclusions: In conclusion, a co-morbid diagnosis of DBD and/or high levels of aggressive symptoms in youth with PBD may be important clinical predictors of variation in treatment response to pharmacotherapy. These findings may help researchers and clinicians develop tailored treatment approaches that optimize symptom and functional outcomes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study is a preliminary report of a group adaptation of child- and family-focused cognitive behavior therapy (CFF-CBT) for pediatric bipolar disorder (PBD). METHODS: CFF-CBT group treatment was provided to twenty six families who had children with a diagnosis of PBD ranging between six- and twelve-years-old. RESULTS: Results indicated that CFF-CBT was feasible and acceptable to families. CFF-CBT resulted in significant improvement in manic, but not depressive, symptoms and in children's psychosocial functioning post-treatment. In addition, although not statistically significant, parents reported an increased ability to cope with their child's illness. Results of this study suggest that group psychosocial treatment provided alongside pharmacotherapy may help attain remission of symptoms, as well as increase overall psychosocial coping and well-being in both children and parents. CONCLUSION: Future work must include a more rigorous test of CFF-CBT in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Objective. This study explores relations between mild parental symptoms of anxiety and depression and the temperament and behavior patterns in preschool age children. Design. Parental report and laboratory observations were collected in a community sample (N = 65) of Head Start and other preschool attendees, ages 3-5 years. Results. Mild parental dysphoria is associated with measures of both child temperament and problem behaviors and these child personality measures vary with parental symptomatology. Mild parental depression was diffusely associated with increased levels of both internalizing and externalizing behavior problems, and with attention and emotion regulatory difficulties in children's temperament. Mild parental anxiety was more circumscribed in its association with child problem behavior but was specifically related to children's temperamental difficulties in attention and emotion regulation. Patterns differentiating association with depression and anxiety symptoms were evident from both parental and observer sources of information. Conclusions. Even mild levels of parental distress may relate to both parental perceptions of child temperament and behavior as well as what is observed by others. [ABSTRACT FROM AUTHOR]

Background: Experience-dependent functional adaptation of nucleus accumbens (NAc) circuitry underlies the development and expression of reward-motivated behaviors. Parvalbumin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (PVINs) within the NAc are required for this process. Perineuronal nets (PNNs) are extracellular matrix structures enriched around PVINs that arise during development and have been proposed to mediate brain circuit stability. However, their function in the adult NAc is largely unknown. Here, we studied the developmental emergence and adult regulation of PNNs in the NAc of male and female mice and examined the cellular and behavioral consequences of reducing the PNN component brevican in NAc PVINs., Methods: We characterized the expression of PNN components in mouse NAc using immunofluorescence and RNA in situ hybridization. We lowered brevican in NAc PVINs of adult mice using an intersectional viral and genetic method and quantified the effects on synaptic inputs to NAc PVINs and reward-motivated learning., Results: PNNs around NAc PVINs were developmentally regulated and appeared during adolescence. In the adult NAc, PVIN PNNs were also dynamically regulated by cocaine. Transcription of the gene that encodes brevican was regulated in a cell type- and isoform-specific manner in the NAc, with the membrane-tethered form of brevican being highly enriched in PVINs. Lowering brevican in NAc PVINs of adult mice decreased their excitatory inputs and enhanced both short-term novel object recognition and cocaine-induced conditioned place preference., Conclusions: Regulation of brevican in NAc PVINs of adult mice modulates their excitatory synaptic drive and sets experience thresholds for the development of motivated behaviors driven by rewarding stimuli., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Neuronal activity-regulated gene expression plays a crucial role in sculpting neural circuits that underpin adaptive brain function. Transcriptional enhancers are now recognized as key components of gene regulation that orchestrate spatiotemporally precise patterns of gene transcription. We propose that the dynamics of enhancer activation uniquely position these genomic elements to finely tune activity-dependent cellular plasticity. Enhancer specificity and modularity can be exploited to gain selective genetic access to specific cell states, and the precise modulation of target gene expression within restricted cellular contexts enabled by targeted enhancer manipulation allows for fine-grained evaluation of gene function. Mounting evidence also suggests that enduring stimulus-induced changes in enhancer states can modify target gene activation upon restimulation, thereby contributing to a form of cell-wide metaplasticity. We advocate for focused exploration of activity-dependent enhancer function to gain new insight into the mechanisms underlying brain plasticity and cognitive dysfunction., Competing Interests: Declaration of interests M.E.G. serves as a member of the Neuron advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Epigenetic regulation of the genome is required for cell-type differentiation during organismal development and is especially important to generate the panoply of specialized cell types that comprise the brain. Here, we review how progressive changes in the chromatin landscape, both in neural progenitors and in postmitotic neurons, orchestrate the timing of gene expression programs that underlie first neurogenesis and then functional neuronal maturation. We discuss how disease-associated mutations in chromatin regulators can change brain composition by impairing the timing of neurogenesis. Further, we highlight studies that are beginning to show how chromatin modifications are integrated at the level of chromatin architecture to coordinate changing transcriptional programs across developmental including in postmitotic neurons., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during postnatal CGN differentiation., Results: We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs., Conclusions: Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development., (© 2024. The Author(s).)

Importance: Adolescence is a period in which mental health problems emerge. Research suggests that the COVID-19 lockdown may have worsened emotional and behavioral health., Objective: To examine whether socioeconomic status was associated with mental health outcomes among youths during the COVID-19 pandemic., Design, Setting, and Participants: The Adolescent Brain Cognitive Development (ABCD) Study is a multisite 10-year longitudinal study of youth neurocognitive development in the US. Recruitment was staggered where the baseline visit (ages 9 to 10 years) occurred from 2016 to 2018, and visits occurred yearly. The COVID-19 lockdown halted research collection during the 2-year follow-up visits (ages 11 to 12 years), but eventually resumed. As some youths already underwent their 2-year visits prior to lockdown, this allowed for a natural experiment-like design to compare prepandemic and intrapandemic groups. Thus, data were gathered from the 1-year follow-up (pre-COVID-19 lockdown for all youths) and the 2-year follow-up, of which a portion of youths had data collected after the lockdown began, to compare whether a period of near social isolation was associated with mental health symptoms in youths. The prepandemic group consisted of youths with a 2-year follow-up visit collected prior to March 11, 2020, and the intrapandemic group had their 2-year follow-up visit after lockdown restrictions were lifted., Main Outcomes and Measures: Assessments included measures on income-to-needs ratio (INR; derived from total household income), the Child Behavior Checklist (a measure of mental health symptomology), and the Family Environmental Scale., Results: The final sample included 10 399 youths; 3947 (52.3%) were male; 2084 (20.3%) were Latinx/Hispanic; 6765 (66.0%) were White; 4600 (44.2%) reported caregiver education levels below a 4-year college degree; and 2475 (26.2%) had INR either below 100% (indicating poverty) or between 100% and less than 200% (near poverty). Among youths in the intrapandemic group, worse mental health symptoms (eg, more total problems, greater depression, and greater anxiety) over time were associated with being from a household with higher socioeconomic status (eg, when comparing individuals who differed by 1 unit on INR between prepandemic and intrapandemic groups from 1-year to 2-year follow-up, their expected difference in total problems score was 0.79 [95% CI, 0.37-1.22]; false discovery rate-corrected P < .001)., Conclusions and Relevance: This cohort study found that the COVID-19 lockdown was associated with disproportionately negative mental health outcomes among youths from higher socioeconomic status backgrounds. Although this study does not shed light on the direct mechanisms driving these associations, it does provide some support for positive outcomes for youths. Future studies are needed to understand whether these associations persist over longer periods of time.

Objective: Approximately 17% of adolescents and young adults will engage in non-suicidal self-injury (NSSI) at least once in their lifetime, leading the World Health Organization to identify self-injury as one of the top five public health concerns for adolescents. Despite the widespread prevalence of this behavior, NSSI continues to be heavily stigmatized in both medical and community settings, deterring many engaged in NSSI from seeking informal support from friends and family as well as formal psychological or psychiatric treatment. In contrast to the low rates of in-person help-seeking for NSSI, online support groups are highly utilized by those engaged in NSSI. Thus, an empirical study of responses to frequent, voluntary disclosure of NSSI on social media is needed to better understand how these communities meet the needs of those who self-injure., Method: The current project used latent Dirichlet allocation to identify frequent and favored themes in response to self-injury content in the largest self-injury group on Reddit (over 100,000 members). Reddit, the 9th most visited website in the world, is a chat-based social media platform that has 430+ million active users and billions of site visits, with current estimates suggesting that ∼63% of the U.S. population are Reddit users., Results: Identified themes included: (1) recovery encouragement; (2) provision of social and instrumental support; and (3) daily realities of living with NSSI. Responses that encouraged recovery received more upvotes on Reddit than any other type of comment., Conclusion: These results can inform evidence-based, person-centered, dimensional treatments for NSSI.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The present article proposes an extension of the concept of adverse childhood experiences (ACEs) to apply to crisis migration - where youth and families are fleeing armed conflicts, natural disasters, community violence, government repression, and other large-scale emergencies. We propose that adverse events occurring prior to, during, and following migration can be classified as crisis-migration-related ACEs, and that the developmental logic underlying ACEs can be extended to the new class of crisis-migration-related ACEs. Specifically, greater numbers, severity, and chronicity of crisis-migration-related ACEs would be expected to predict greater impairments in mental and physical health, poorer interpersonal relationships, and less job stability later on. We propose a research agenda centered around definitional clarity, rigorous measurement development, prospective longitudinal studies to establish predictive validity, and collaborations among researchers, practitioners, and policymakers., (© 2023. The Author(s).)

Little is known about the impact of sociocultural stressors such as acculturative stress on self-rated health among Hispanics. We aimed to examine (a) associations between acculturative stress and self-rated health, and (b) the moderating effects of the community of settlement (i.e., Maricopa County, AZ and Miami-Dade County, FL) and social support on the association between acculturative stress and self-rated health. A hierarchical multiple regression model and moderation analyses were conducted using a cross-sectional sample of 200 Hispanic emerging adults from Arizona and Florida. Findings indicate that higher levels of pressure to acculturate are associated with lower levels of self-rated health. Community of settlement functioned as a moderator whereby pressure to acculturate was only associated with lower levels of self-rated health in Maricopa County. Lastly, a three-way interaction indicated that emotional social support mitigated the association between pressure to acculturate and self-rated health in Maricopa County. This study highlights the importance of accounting for community of settlement when examining associations between acculturative stress and health-related outcomes. A finding that may have implications for interventions is that social support may help to counteract the effects of acculturative stress., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Indigenous people experience health disparities, including higher rates of substance use disorders (SUDs). Digital therapeutics are a growing platform for treatment services and have the potential to expand access to culturally responsive interventions for Indigenous people. As one of the first randomized controlled trials for SUDs for American Indian and Alaska Native (AI/AN) adults, the aim of this study was to pilot test the efficacy of a culturally tailored intervention among urban Indigenous adults., Methods: The study used a randomized controlled parallel design of 12 weeks of treatment-as-usual (TAU) (n = 26) versus TAU + Therapeutic Education System-Native Version (TES-NAV) (n = 27) with follow-up assessments at end of treatment and week 24 in an urban outpatient addiction treatment program for Native American adults. TAU consisted of individual/group counseling and cultural activities. The TES-NAV arm comprised TAU + 26 self-directed culturally tailored digital skills-based modules grounded in the community reinforcement approach with contingency management for abstinence and module completion. Primary outcome was longest consecutive weeks of abstinence from drugs and heavy drinking measured using self-report (Timeline Followback) and urine alcohol and drug toxicology screen during 12 weeks of treatment. Secondary outcomes were percent days abstinence during and posttreatment, coping strategies, social connectedness, and substance use and sexual risk behaviors., Results: The study enrolled fifty-three (52.8 % male) AI/AN adults seeking treatment for a SUD. Although the study did not detect a benefit of TAU+TES-NAV over TAU on the primary outcome (Median = 2 consecutive weeks of abstinence for both arms) at end of treatment (treatment effect: Z = -0.78, p = 0.437), TAU+TES-NAV participants did demonstrate significantly greater percent days of abstinence at the week 24 follow-up (69.3 % versus 49.0 % for TAU; t = 2.08, p = 0.045) and significantly greater change in social connectedness mean score, baseline to week 12 (Z = -2.66, p = 0.011), compared to TAU. The study detected no differences between treatment arms for coping strategies or risk behaviors., Conclusion: The addition of TES-NAV to TAU did not significantly improve consecutive weeks of abstinence from drugs or heavy drinking; however, several secondary findings suggest promise for a culturally tailored digital therapeutic SUD intervention among urban Indigenous people., Clinical Trials: GOV REGISTRATION: #NCT03363256., Competing Interests: Declaration of competing interest Dr. Venner provides training and consultation in evidence-based treatments for fee. Dr. Venner has a conflict-of-interest management plan at her academic institution. Dr. Marsch is affiliated with the company that developed the Therapeutic Education System, the company that deploys reSET®, as well as Click Therapeutics and Square2 Systems. These relationships are extensively managed by her academic institution. The remaining authors have no competing interests to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell imaging and single-molecule tracking are sensitive methods to quantify the DNA binding affinity and diffusion dynamics of nuclear proteins. In this issue of Genes & Development , Zhou and colleagues (pp. 883-900) used these imaging methods to quantitatively describe the partial loss of DNA binding resulting from a novel pathological MECP2 mutation with intermediate disease severity. These data demonstrate how single-molecule tracking can advance understanding of the molecular mechanisms connecting MECP2 mutations with Rett syndrome pathophysiology., (© 2023 West; Published by Cold Spring Harbor Laboratory Press.)

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we assessed expression of PV-enriched, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants to explore the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The field of clinical child and adolescent psychology is in critical need of transformation to effectively meet the mental health needs of marginalized and minoritized youth. As a field, we must acknowledge and grapple with the racist and colonial structures that support the scientific foundation, education and training of psychologists, and the service systems currently in place to support youth mental health in this country. We argue that to effectuate change toward a discipline that centers inclusivity, intersectionality, anti-racism, and social justice, there are four interrelated systems, structures, or processes that currently support racial inequity and would need to be thoroughly examined, dismantled, and re-imagined: (1) the experience of mental health problems and corresponding access to quality care; (2) the school-to-mental healthcare pathway; (3) the child welfare and carceral systems; and (4) the psychology workforce. A "call to action" is issued to address structural racism in these systems and recommendations are provided to guide clinicians, health care systems, educators, welfare and carceral systems, and those involved in training and retaining psychologists in the field in actions they can take to contribute to transformation. We assert that change will only occur when we individually and collectively take responsibility for the roles we have as agents for radical change within the personal and professional contexts in which we live and work. Only then will the field of clinical child and adolescent psychology be able to address the youth mental health crisis and effectively promote the health and well-being of all children.

Background: Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors., Methods: A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic (gamma-aminobutyric acidergic)-synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons, and they coexpress the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single-nucleus RNA sequencing., Results: Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb coexpress markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder, which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein netrin-G2 as a marker of LHb GAD2+/VGLUT2+ neurons and a gene product that may contribute to their target projections., Conclusions: These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb., (© 2023 The Authors.)

Background: In recent years public health research has shifted to more strengths or asset-based approaches to health research but there is little understanding of what this concept means to Indigenous researchers. Therefore our purpose was to define an Indigenous strengths-based approach to health and well-being research., Methods: Using Group Concept Mapping, Indigenous health researchers (N = 27) participated in three-phases. Phase 1: Participants provided 218 unique responses to the focus prompt "Indigenous Strengths-Based Health and Wellness Research…" Redundancies and irrelevant statements were removed using content analysis, resulting in a final set of 94 statements. Phase 2: Participants sorted statements into groupings and named these groupings. Participants rated each statement based on importance using a 4-point scale. Hierarchical cluster analysis was used to create clusters based on how statements were grouped by participants. Phase 3: Two virtual meetings were held to share and invite researchers to collaboratively interpret results., Results: A six-cluster map representing the meaning of Indigenous strengths-based health and wellness research was created. Results of mean rating analysis showed all six clusters were rated on average as moderately important., Conclusions: The definition of Indigenous strengths-based health research, created through collaboration with leading AI/AN health researchers, centers Indigenous knowledges and cultures while shifting the research narrative from one of illness to one of flourishing and relationality. This framework offers actionable steps to researchers, public health practitioners, funders, and institutions to promote relational, strengths-based research that has the potential to promote Indigenous health and wellness at individual, family, community, and population levels., (© 2023. The Author(s).)

The functional maturation of neurons is a prolonged process that extends past the mitotic exit and is mediated by the chromatin-dependent orchestration of gene transcription programs. We find that expression of this maturation gene program in mouse cerebellar granule neurons (CGNs) requires dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), demonstrating a function for this chromatin modification beyond its role in cell fate specification. The developmental loss of H3K27me3 at promoters of genes activated as CGNs mature is facilitated by the lysine demethylase and ASD-risk gene, Kdm6b. Interestingly, inhibition of the H3K27 methyltransferase EZH2 in newborn CGNs not only blocks the repression of progenitor genes but also impairs the induction of mature CGN genes, showing the importance of bidirectional H3K27me3 regulation across the genome. These data demonstrate that H3K27me3 turnover in developing postmitotic neurons regulates the temporal coordination of gene expression programs that underlie functional neuronal maturation., Competing Interests: VR, FL, MM, UC No competing interests declared, AW Reviewing editor, eLife, (© 2023, Ramesh, Liu et al.)

American Indian and Alaska Native (AIAN) communities have higher rates of substance use than other racial and ethnic groups. Substance use disorder (SUD) is tied to the increased risk of experiencing homelessness. National policies have also led to the disproportionate rates of homelessness among AIAN communities. However, specific experiences related to the occurrence of SUD and homelessness among AIAN in California, as well as seeking and accessing SUD treatment, are not well understood. This study explored potential SUD risk and resilience factors for AIANs experiencing homelessness and their experiences when seeking services for SUD. Nineteen interviews were conducted in northern, central, and southern California. Thematic analysis was used for these data. The five primary codes were: (1) risk factors for SUD, (2) resilience related to SUD service seeking, (3) services available, (4) barriers accessing services, and (5) services needed. Based on the results, themes for risk were trauma, mental health, and community conditions. Themes for resilience were identified at individual and community levels and included personal motivation and community support and inclusiveness. Themes for services available were limited knowledge about service types and services' location. The themes for barriers accessing services were identified at internal and external levels, and included lack of readiness and transportation challenges, respectively. Themes for services needed included continuum of care, integrated care, and culturally sensitive services. Findings highlight the importance of addressing the potential risk factors and service needs of AIANs experiencing homelessness to provide comprehensive and culturally sensitive services to reduce substance use.

Background: Randomized clinical trials (RCTs) enrolling pediatric populations often struggle with recruitment. Engaging healthcare providers in the recruitment process may increase patients' and caregivers' willingness to participate in research. The purpose of this study was to understand the perspectives of pediatric subspecialty healthcare providers considering recruiting patients to participate in an mobile health (mHealth) RCT., Methods: We conducted 9 semi-structured interviews and 1 focus group with a total of N  = 11 providers from various disciplines before the initiation of an mHealth RCT addressing medication nonadherence. Then, we conducted 5 follow-up interviews and 1 follow-up focus group with a total of 8 of these providers several months later. We used thematic analysis to generate themes describing providers' views of the RCT and patient recruitment., Results: Providers indicated that they were willing to recruit for this study because they believed that the intervention sought to address a significant problem. They also thought it made sense to intervene using technology for this age group. However, many providers thought that certain patients (e.g., those with mild, shorter-lasting adherence difficulties) were the most appropriate to recruit. They described how keeping the trial front of mind facilitated recruitment, and they advised researchers to use strategies to promote their ongoing awareness of the study if conducting similar research in the future., Conclusion: Pediatric healthcare providers are important stakeholders in mHealth intervention research. Engaging them in participant recruitment is a complex endeavor that might promote patient enrollment, but their views of research and demanding clinical roles are important to understand when designing study procedures., Competing Interests: None of the authors have a conflict of interest to disclose., (©2023PublishedbyElsevierInc.)

Objective: American Indian and Alaska Native (AIAN) youth demonstrate significant substance use and mental health disparities and represent a highly underserved population with regard to effective services. A community-based needs assessment study of urban and rural AIAN youth throughout California was conducted to inform the development of community-based, culturally relevant opioid and substance use services. This study examined AIAN youth experiences with opioid and other substance use disorders (OUD/SUD) in their communities, utilization of existing programs, and service system recommendations. Method: Fifteen focus groups were conducted in partnership with urban and rural/reservation health programs, and AIAN serving community-based organizations throughout California with youth ranging from 13 to 18 years of age. Focus groups were recorded and professionally transcribed, then coded using NVivo qualitative data analysis software. An a priori coding structure was refined through a data-informed, iterative process until a final coding structure was agreed upon to characterize data. Results: Findings demonstrate the need for OUD/SUD services that integrate cultural beliefs and practices, incorporate attention to family and community risk and resiliency factors, provide effective outreach and education, and focus on the development of holistic wellness and positive development for AIAN youth. This study also provides a model for conducting a needs assessment using community-based participatory methods to inform effective service development that more directly responds to community-identified needs. Conclusion: Findings indicate that future services and interventions should incorporate a focus on promoting overall wellness and positive youth development in order to prevent or promote recovery from opioid or other substance abuse. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities and dysmorphic facies. RMNS is caused by de novo heterozygous mutations in the histone linker gene H1-4; however, mechanisms underlying impaired neurodevelopment in RMNS are not understood. All reported mutations associated with RMNS in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified new variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports and strengthen the support of pathogenicity of H1.4 CFT. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wild-type or H1.4 CFT protein in rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~ 400 genes altered in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT also showed reduced neuronal activity on multielectrode arrays. These data are the first to characterize the transcriptional and functional consequence of H1.4 CFT in neurons. Our data provide insight into causes of neurodevelopmental impairments associated with frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of histone H1.4 in neurons., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This paper examines substance and behavioral addictions among American Indian and Alaska Natives (AIAN) to identify the structural and psychosocial risk and cultural protective factors that are associated with substance use and behavioral addictions., Methods: Five databases were used to search for peer reviewed articles through December 2021 that examined substance and behavioral addictions among AIANs., Results: The literature search identified 69 articles. Numerous risk factors (i.e., life stressors, severe trauma, family history of alcohol use) and protective factors (i.e., ethnic identity, family support) influence multiple substance (i.e., commercial tobacco, alcohol, opioid, stimulants) and behavioral (e.g., gambling) addictions., Conclusions: There is a dearth of research on behavioral addictions among AIANs. Unique risk factors in AIAN communities such as historical trauma and socioeconomic challenges have interfered with traditional cultural resilience factors and have increased the risk of behavioral addictions. Future research on resilience factors and effective prevention and treatment interventions could help AIANs avoid behavioral addictions.

Background: Individuals with depression often demonstrate an altered peripheral inflammatory profile, as well as emotion perception difficulties. However, correlations of inflammation with overall depression severity are inconsistent and inflammation may only contribute to specific symptoms. Moreover, measurement of the association between inflammation and emotion perception is sparse in adolescence, despite representing a formative window of emotional development and high-risk period for depression onset., Methods: Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were measured in 34 adolescents aged 12-17 with DSM-IV depressive disorders (DEP) and 29 healthy controls (HC). Participants were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and symptom subscales were extracted based on factor analysis. Participants also completed a performance-based measure of emotion perception, the Facial Emotion Perception Test (FEPT), which assesses the accuracy of categorizing angry, fearful, sad, happy, and neutral facial emotions., Results: IL-6 and TNF-α correlated with reported depressed mood and somatic symptoms, respectively, but not total CDRS-R score, anhedonia or observed mood, across both DEP and HC. DEP demonstrated lower accuracy for identifying angry facial expressions. Higher IL-6 was inversely related to accuracy and discrimination of angry and neutral faces across all participants. IL-1β was associated with reduced discrimination of fearful faces., Conclusions: Inflammatory markers were sensitive to affective and somatic symptoms of depression and processing of emotional threat in adolescents. In particular, IL-6 was elevated in depressed adolescents and therefore may represent a specific target for modulating depressive symptoms and emotion processing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

CRISPR-Cas9 technologies have dramatically increased the ease of targeting DNA sequences in the genomes of living systems. The fusion of chromatin-modifying domains to nuclease-deactivated Cas9 (dCas9) has enabled targeted epigenome editing in both cultured cells and animal models. However, delivering large dCas9 fusion proteins to target cells and tissues is an obstacle to the widespread adoption of these tools for in vivo studies. Here, we describe the generation and characterization of two conditional transgenic mouse lines for epigenome editing, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. By targeting the guide RNAs to transcriptional start sites or distal enhancer elements, we demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo, and in T cells and fibroblasts ex vivo. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expression in vivo., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn't working well-whether to optimize the treatment already begun or to add the other treatment., Methods: This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8-17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first ("Main Effect 1"). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment ("Main Effect 2"). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone., Discussion: Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders., Trial Registration: This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275 .

Neurons undergo dynamic changes in their structure and function during brain development to form appropriate connections with other cells. The rodent cerebellum is an ideal system to track the development and morphogenesis of a single cell type, the cerebellar granule neuron (CGN), across time. Here, in vivo electroporation of granule neuron progenitors in the developing mouse cerebellum was employed to sparsely label cells for subsequent morphological analyses. The efficacy of this technique is demonstrated in its ability to showcase key developmental stages of CGN maturation, with a specific focus on the formation of dendritic claws, which are specialized structures where these cells receive the majority of their synaptic inputs. In addition to providing snapshots of CGN synaptic structures throughout cerebellar development, this technique can be adapted to genetically manipulate granule neurons in a cell-autonomous manner to study the role of any gene of interest and its effect on CGN morphology, claw development, and synaptogenesis.

It is a striking paradox that the activation of NMDA-type glutamate receptors (NMDARs) can both promote neuronal survival and induce excitotoxic cell death. Yet the molecular mechanisms that distinguish these cellular consequences have remained obscure. A recent study by Yan et al. (2020) reveals a novel interaction between NMDARs and TRPM4 that is required for NMDAR-induced neuronal death. Small molecule disruption of this interaction reduces excitotoxicity in stroke without blocking physiological NMDAR signaling., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective : To evaluate the oncological outcome at 5-year follow-up after laparoscopic cryoablation (LCA) for small renal masses (SRMs), as there is an increasing interest in ablative therapy for cT1a renal tumours due to the rising incidence of SRMs, the trend towards minimally invasive nephron-sparing treatments, and the ageing population. Patients and methods : Between 2004 and 2015, 233 consecutive LCA were performed in 219 patients for SRMs at two referral centres. We only included those patients with ≥5 years of follow-up ( n = 165) in a prospectively maintained database. A descriptive analysis was conducted for pre-, peri- and postoperative characteristics. A Kaplan-Meier analysis assessed overall (OS), disease-specific (DSS), and recurrence-free survival (RFS). Results : The median (interquartile range [IQR]) age of our patient cohort was 68 (60.5-76) years. The median (IQR) body mass index was 26.2 (23.8-29) kg/m 2 , and the median (IQR) Charlson Comorbidity Index score corrected for age was 4 (2.5-6). The median (IQR) tumour diameter was 28 (21-33) mm. In all, 15% developed a complication in the first 30 days after LCA, of which 1% had a major complication (Clavien-Dindo Grade ≥III). The median (IQR) preoperative estimated glomerular filtration rate (eGFR) was 82.5 (65-93.75) mL/min/1.73 m 2 . The median eGFR decreased by 16.4% and 15.2% at the 3-month and 5-year follow-up, respectively. Persistence was found in 1%, local recurrence in 2%, and systemic progression in 4%. The OS, DSS, and RFS were 74%, 96.9% and 95.4%, respectively. Conclusion : LCA is a safe and effective treatment for SRMs in selected cases and shows good oncological outcomes after 5 years of follow-up, with only 1% developing a major complication., Competing Interests: All authors declare that they have no conflicts of interest., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

N -Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor ( Bdnf ) and activity-regulated cytoskeleton-associated protein ( Arc ). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Chen et al.)

Cognitive-behavioral therapy (CBT) alleviates symptoms of depression in youth with bipolar disorder (BD) and major depressive disorder (MDD). Empirical research has linked inflammatory markers to depressive symptoms and acute psychosocial stress; however, a gap remains as to whether immune response to stress may serve as a putative mechanism of treatment. This preliminary pilot study determined the modest feasibility of assessing psychobiological response to stress as a predictor of CBT outcomes for youth with mood disorders. We evaluated whether participation in a 10-session group-CBT intervention for mood disorders altered inflammatory response to a laboratory psychosocial stress induction and if this alteration in immune stress responsivity was related to a decrease in depressive symptoms. Thirty-four youth (age M = 15.03, SD = 1.91) diagnosed with BD or MDD participated in a 10-session CBT group and pre- and post-group assessments; twenty-eight participants who completed the group had usable cytokine data. Pre- and post-group assessments included stress induction with the Trier Social Stress Test (TSST) during which inflammatory cytokines were measured at baseline (time 0) and after the TSST at 30, 60, and 90 min. Results suggest it is modestly feasible to measure immune response to stress alongside CBT treatment for adolescent mood disorders. Our findings were mixed; across seven cytokines, hierarchical linear models indicated two cytokines, IL6 and IL12, were sensitive to acute laboratory stress. We also found significant correlations between life stress, inflammation, and depression both pre- and post- CBT group. Inflammation pre-group, as measured by IL12 and IL1 β predicted depressive symptoms following treatment. Although we did not find significant within-subject reductions in inflammation, chronic stress predicted changes in IL β, signaling the central role of chronic stress. This study offers preliminary evidence that immune responsivity to stress induction could serve as a mechanism of treatment for mood disorders in youth, indicating a potential marker for more personalized model of healthcare., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Transcriptional enhancers are regulatory DNA elements that underlie the specificity and dynamic patterns of gene expression. Over the past decade, large-scale functional genomics projects have driven transformative progress in our understanding of enhancers. These data have relevance for identifying mechanisms of gene regulation in the CNS, elucidating the function of non-coding regulatory sequences in neurobiology and linking sequence variation within enhancers to genetic risk for neurological and psychiatric disorders. However, the sheer volume and complexity of genomic data presents a challenge to interpreting enhancer function in normal and pathogenic neurobiological processes. Here, to advance the application of genome-scale enhancer data, we offer a primer on current models of enhancer function in the CNS, we review how enhancers regulate gene expression across the neuronal lifespan, and we suggest how emerging findings regarding the role of non-coding sequence variation offer opportunities for understanding brain disorders and developing new technologies for neuroscience.

For more than 40 years after its discovery, histone methylation was thought to be largely irreversible. However, the first histone demethylase (HDM) was identified in 2004, challenging this notion. Since that time, more than 20 HDMs have been identified and characterized, and many have been shown to have critical roles in organismal development, cell fate, and disease. Here, we highlight some of the recent advances in our understanding of the function of HDMs in the context of neuronal development, plasticity, and disease. We focus, in particular, on molecular genetic studies of LSD1, Kdm6b, and Kdm5c that have elucidated both enzymatic and non-enzymatic gene regulatory functions of these HDMs in neurons., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A new study in Cell (Brigidi et al., 2019) shows that local dendritic versus somatic translation of the neuronal activity-inducible transcription factor NPAS4 drives the formation of distinct heterodimers that enable stimulus-specificity to be encoded into the pattern of NPAS4 binding across the genome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is presumed that Indigenous researchers are optimally positioned to conduct research about or within their own or other Indigenous communities. However, these researchers may still experience challenges, barriers, and distressing events that are important to identify. Qualitative inquiry may be a particularly vulnerable context for Indigenous researchers given the nature of data collection methods and an emphasis on researcher-participant relationships. This paper details the personal reflections of two American Indian (AI) researchers who carried out qualitative research focused on AI issues and/or communities. The first project examined undergraduate students' opinions of the use of AI imagery in the form of a race-based university mascot. The second was a study of the mental health needs of AI youth and families in an urban community. Several themes characterized both of their experiences and might be generalizable to others working in these contexts: (a) coping with racism and microaggressions; (b) the role and impact of identity politics; (c) community insider/outsider tension; and (d) managing personal distress associated with the research topics and process. These themes are discussed to illuminate ways that Indigenous researchers, engaged in research on Indigenous topics and/or with Indigenous communities, are challenged and affected by their work., (© 2019 Society for Community Research and Action.)

Whether dynamic changes in genome architecture underlie transcriptional and functional plasticity in mature neurons has been technically challenging to address. A recent study (Yamada et al., Nature, 2019) exploited experimental advantages of the cerebellum to reveal cell type-specific changes in chromatin architecture that coordinate neural activity-induced changes in gene transcription and contribute to sensorimotor learning., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Pro-inflammatory cytokines have been linked to depression, early childhood trauma, and impairment in executive function in adults. Whether these links are present during adolescence, a time when vulnerability to depression is heightened, a point more proximal to childhood trauma, and a critical period of brain development, is not well understood., Method: Serum levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α) were measured in 70 adolescents aged 12-17, including 40 with a DSM-IV depressive disorder (DEP), a sub-set (n = 22) of whom reported a history of childhood trauma (DEP-T), and 30 healthy controls (HCs). Participants completed performance-based (Parametric Go/No-Go Task) and observer-rated (Behavior Rating Inventory of Executive Function) measures of executive function. Procedures were conducted at a subspecialty clinic (Dec 2015-June 2017)., Results: IL-6 was elevated in DEP and DEP-T adolescents compared to controls (p = .014) and TNF-α was elevated in DEP participants only (p = .040) compared to controls, whereas no group differences were found in IL-1β (p = .829). Additionally, DEP-T participants demonstrated relative deficits in performance-based (p = .044) and observer-rated inhibitory control (p = .049) compared to controls. Across the whole sample, TNF-α was associated with performance-based (r = -0.25, p = .039) and observer-rated (r = 0.32, p = .009) inhibitory control deficits. In subgroup analyses, TNF-α was associated with increased observer-rated inhibitory deficits in DEP, and at the trend level, with reduced inhibitory control performance in DEP-T., Conclusions: The current results suggest that inflammation may be a marker of disease processes in adolescent depression. Though longitudinal studies are needed, depressed adolescents with childhood trauma exposure appear to constitute a uniquely vulnerable group in terms of objective risk for executive dysfunction. Immune dysregulation may partly contribute to this risk., (Copyright © 2019. Published by Elsevier Ltd.)

Most adaptive behaviors require precise tracking of targets in space. In pursuit behavior with a moving target, mice use distance to target to guide their own movement continuously. Here, we show that in the sensorimotor striatum, parvalbumin-positive fast-spiking interneurons (FSIs) can represent the distance between self and target during pursuit behavior, while striatal projection neurons (SPNs), which receive FSI projections, can represent self-velocity. FSIs are shown to regulate velocity-related SPN activity during pursuit, so that movement velocity is continuously modulated by distance to target. Moreover, bidirectional manipulation of FSI activity can selectively disrupt performance by increasing or decreasing the self-target distance. Our results reveal a key role of the FSI-SPN interneuron circuit in pursuit behavior and elucidate how this circuit implements distance to velocity transformation required for the critical underlying computation.

Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. Exactly how histone acetylation modulates transcription of these genes has remained unknown. We used single-cell in situ transcriptional analysis to show that Fos and Npas4 are transcribed in stochastic bursts in mouse neurons and that membrane depolarization increases mRNA expression by increasing burst frequency. We then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins to mimic or block activity-induced histone acetylation locally at enhancers. Adding histone acetylation increased Fos transcription by prolonging burst duration and resulted in higher Fos protein levels and an elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency and impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus, activity-inducible histone acetylation tunes the transcriptional dynamics of experience-regulated genes to affect selective changes in neuronal gene expression and cellular function., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)